CN101851198A - Preparation method of ciprofloxacin hydrochloride - Google Patents
Preparation method of ciprofloxacin hydrochloride Download PDFInfo
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- CN101851198A CN101851198A CN200910158876A CN200910158876A CN101851198A CN 101851198 A CN101851198 A CN 101851198A CN 200910158876 A CN200910158876 A CN 200910158876A CN 200910158876 A CN200910158876 A CN 200910158876A CN 101851198 A CN101851198 A CN 101851198A
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Abstract
The invention discloses a preparation method of ciprofloxacin hydrochloride. The existing synthesis method generally uses isoamyl alcohol and the like as solvent, thus having the problems of strong smell, difficult biodegradation and higher environmental pollution. If the solvent such as the isoamyl alcohol and the like is used, more alkali insoluble substances and acidic insoluble substances are generated in recovery after the reaction, so that the insoluble substances are needed to be treated by purification through the steps such as alkali-dissolving heat-filtering call-back throw filter, acidic-dissolving heat-filtering call-back throw filter, salifying decoloration heat-filtering and the like, the process route is longer, and the product yield is lower. The preparation method of the ciprofloxacin hydrochloride selects the proper solvent as reaction medium, firstly leads cyclopropane carboxylic acid and piperazine to have piperazine reduction reaction and then leads the reaction product to be salified together with hydrochloric acid. In the reaction process, less alkali insoluble substances and acidic insoluble substances are generated in the reaction process, and the ciprofloxacin hydrochloride can be obtained by salifying decoloration heat-filtering, separation by crystallization, throw filter, rinsing and drying after being directly cooled and leached, so that the time for occupying equipment and the time of working procedures are shortened, and the production efficiency of a workshop is improved.
Description
Technical field
The present invention relates to pharmaceutical field, specifically a kind of preparation method of ciprofloxacin HCl.
Background technology
Fluoroquinolones is efficient with it, the antimicrobial characteristic of wide spectrum, low toxicity, is obtaining immense success aspect the clinical anti-infective therapy, is wherein outstanding kind by Bayer A.G in the ciprofloxacin HCl of development in 1981.Ciprofloxacin HCl, English name: Ciprofloxacin Hydrochloride, molecular formula: C
17H
18FN
3O
3HClH
2O, molecular weight: 385.82, structural formula is as follows:
With the cyclopropyl carboxylic acid be in the raw material synthetic hydrochloric acid Ciprofloxacin effectively the method for medicinal ingredients Ciprofloxacin mainly contain:
1) direct substitution method: piperazine and cyclopropyl carboxylic acid are reacted (document: Ger Offen1982,3033157 in polar solvent; CA 1982,97:55793u; Day disclosure special permission 84-204194, CA 1985,102:185097c).
2) N-ethoxycarbonyl piperazine and cyclopropyl carboxylic acid react in polar solvent in the presence of acid binding agent, make Ciprofloxacin (document Span 1990,2013307 through hydrolysis again; CA 1985,102:185097c).
3) with 1, two (trimethyl silicon based) piperazines of 4-and cyclopropyl carboxylic acid carry out substitution reaction, again dehydration (Span1986,543209; CA 1987,106:84647).
4) with cyclopropyl carboxylic acid and boron trifluoride (or its complex compound) reaction, generate intermediate, with the piperazine reaction, hydrolysis makes Ciprofloxacin, and (CA 1989,111:39385q again; CA 1989,110:73110d).
Above-mentioned direct substitution method is carried out nucleophilic substitution reaction with piperazine and cyclopropyl carboxylic acid, is present comparatively general industrialization synthetic method, and this method synthetic route is as follows:
Material after above-mentioned the reacting completely is distilled, reclaim solvent and piperazine, in residuum, add an amount of liquid caustic soda again, moltenly add activated carbon decolorizing after clear, filtered while hot, with the hydrochloric acid readjustment, centrifugation after product is separated out fully; Centrifugal resulting solid is placed still, add the acid dissolving, use activated carbon decolorizing at a certain temperature, filtered while hot adds the alkali readjustment, and product is separated out the back centrifugation fully; With solid and the hydrochloric acid salify that makes at last,, make the ciprofloxacin HCl finished product through decolouring purifying, cooling crystallization, centrifugal, rinsing and drying.There is following shortcoming in this preparation route: solvent commonly used is primary isoamyl alcohol, DMSO, DMF etc. when 1) contracting piperazine at present, exists smell big, the biological degradation difficulty, and environmental pollution is bigger; 2), temperature requiredly during recovery be higher than 120 ℃ mostly, and recovery time is longer, and side reaction easily takes place, and influences quality product and outward appearance in removal process because the solvent boiling point that uses is higher; 3) if use above-mentioned solvent, finish to produce more alkali insolubles and acid non-soluble substance when reclaim the back in reaction, must get rid of filter by the molten heat filter readjustment of alkali, the molten heat filter of acid readjustment gets rid of steps such as filter and the hot filter of salify decolouring and carries out purification process, not only operational path is long partially, and product yield is lower.
Summary of the invention
Technical problem to be solved by this invention is to overcome the defective that above-mentioned prior art exists, a simple and direct operational path for preparing ciprofloxacin HCl from cyclopropyl carboxylic acid is provided, it adopts a suitable solvent as the reaction medium piperazine reaction of contracting, to shorten postprocessing working procedures, reduce environmental pollution, improve the quality of products and yield.
For this reason, the technical solution used in the present invention is as follows: the preparation method of ciprofloxacin HCl, its step is as follows: a) cyclopropyl carboxylic acid is added in the organic solvent, and the adding piperazine,, reacted 3～8 hours down as acid binding agent with alkali at 60～120 ℃, the monitoring cyclopropyl carboxylic acid is residual less than 2% o'clock termination reaction, stirring is cooled to 0～30 ℃, leaves standstill suction filtration; B) add water and hydrochloric acid in the products therefrom toward a) step, under agitation be warming up to molten clearly, add activated carbon decolorizing, filtered while hot, and transfer filtrate pH to 2～4 with hydrochloric acid, and the cooling crystallization filters, rinsing, and drying makes ciprofloxacin HCl;
Above-mentioned a) the organic solvent described in the step is 2-Pyrrolidone, N, N-N,N-DIMETHYLACETAMIDE (DMAc), N, a kind of and mixed solvent more than two kinds in dinethylformamide (DMF), propylene carbonate, diethyl carbonate, 1-Methyl-2-Pyrrolidone, N-ethyl pyrrolidone, ethylene carbonate, propyl carbinol, the n-hexyl alcohol.
Described organic solvent is preferably N, the mixed solvent of N-N,N-DIMETHYLACETAMIDE and propyl carbinol, the volume ratio of N,N-dimethylacetamide and propyl carbinol are 1: 9-5: 5, the acid non-soluble substance that obtains with this preferred mixed solvent still less is about and utilizes 1/3 of acid non-soluble substance that other solvent obtains.
The present invention selects for use suitable solvent as reaction medium, and the contract piperazine reaction of first cyclopropyl carboxylic acid and piperazine is then with the hydrochloric acid salify.Adopt this solvent to have the following advantages: a) this solvent odor is less, is easy to biological degradation, belongs to environmentally friendly organic solvent; B) polarity is moderate, and the piperazine that contracts reaction can better be carried out under 50～120 ℃; C) do not need after reacting completely high temperature to reclaim solvent, directly cool off suction filtration, simple and convenient, avoid high-temperature operation, cut down the consumption of energy and, improve the quality of product the requirement of equipment; D) the alkali insolubles, the acid non-soluble substance that produce in the reaction process are all less, directly behind the cooling suction filtration, separate out, get rid of filter, rinsing and smoke and to make ciprofloxacin HCl through the filter of salify decolouring heat, crystallization, shortened hold facility and activity time, improved Workshop Production efficient.Reaction scheme of the present invention is as follows:
The piperazine main reaction of contracting:
The piperazine side reaction 1 of contracting:
The piperazine side reaction 2 of contracting:
Salt-forming reaction:
Above-mentioned method, a) alkali described in the step is salt of wormwood, yellow soda ash, saleratus, sodium bicarbonate, triethylamine, Tetramethyl Ethylene Diamine or pyridine.
The invention provides a kind of preparation method of ciprofloxacin HCl, this method has following beneficial effect:
1) smell is little, the readily biodegradable solvent owing to having adopted, and has reduced environmental pollution, for cleaner production is laid a good foundation; 2) be reflected under the lower temperature and carry out, improved the selectivity of reaction, reduced the generation of side reaction 1, contained that effectively main by product is the generation of the by product chlorine piperazine acid that replaces of dystopy; 3) reduce the generation of side reaction 2, thereby alkali insolubles, acid non-soluble substance are less, so can shorten post-processing step, have simplified production technique; 4) adopt during product separation filter type to substitute the mode of high temperature recovery solvent, make the outward appearance and the quality index of product all have clear improvement, product yield height, Functionality, quality and appealing design, outward appearance is a white, quality index meets the EP6.0 standard, has obvious social and economic benefit.
The invention will be further described below in conjunction with embodiment.
Embodiment
Embodiment 1
(1) piperazine that contracts
30g cyclopropyl carboxylic acid (0.1065mol), 50g piperazine (0.5805mol), 150ml 2-Pyrrolidone are dropped in the clean there-necked flask of 250ml.Stir heat temperature raising to 70～80 ℃, the about 3h of timing insulation.The monitoring of sampling liquid phase, carboxylic acid remained being controlled at below 1.5%.Insulation reaction finishes, and is cooled to 28 ± 2 ℃.Cooling is finished, and leaves standstill 3 hours, and suction filtration with 30ml * 3 medicinal alcohol rinsings, gets the wet crude product of 55～65g.
(2) salify
Above-mentioned thick wet product are dropped in the 250ml there-necked flask, add 150g water, stirring is warming up to 85 ℃, and dripping hydrochloric acid is molten substantially clear to system, adds the 1.0g gac, stirred 30 minutes, decolouring is finished, filtered while hot to the clean there-necked flask of another 250ml, acid non-soluble substance 0.8g, filter is finished, and dripping hydrochloric acid is transferred system pH=2.5～3.0 while stirring.Transfer and finish, slowly be cooled to 35 ± 2 ℃, a large amount of crystal are separated out.Suction filtration, 20ml * 2 medicinal alcohol rinsings gets 45g ciprofloxacin HCl wet finished product.Smoke 31.5g ciprofloxacin HCl finished product (0.0816mol), molar yield is 76.6%.
Embodiment 2
Be with the 2-Pyrrolidone to be solvent with the difference of embodiment 1, when contracting piperazine, add K
2CO
3Be acid binding agent, the finished product molar yield is 77.8%.
Embodiment 3
(1) piperazine that contracts
30g cyclopropyl carboxylic acid (0.1065mol), 40g piperazine (0.4644mol), 120ml N-ethyl pyrrolidone are dropped in the clean there-necked flask of 250ml.Stir heat temperature raising to 110～115 ℃, the about 10h of timing insulation.The monitoring of sampling liquid phase, carboxylic acid remained being controlled at below 1.5%.Insulation reaction finishes, and is cooled to 20 ± 2 ℃.Cooling is finished, and leaves standstill 3 hours, and suction filtration with 30ml * 3 medicinal alcohol rinsings, gets the wet crude product of 65～70g.
(2) salify
Above-mentioned thick wet product are dropped in the 250ml there-necked flask, add 150g water, stirring is warming up to 85 ℃, and dripping hydrochloric acid is molten substantially clear to system, adds the 1.5g gac, stirred 30 minutes, decolouring is finished, filtered while hot to the clean there-necked flask of another 250ml, acid non-soluble substance 0.9g, filter is finished, and dripping hydrochloric acid is transferred system pH=1.5～3.0 while stirring.Transfer and finish, slowly be cooled to 20 ± 2 ℃, a large amount of crystal are separated out.Suction filtration, 20ml * 2 medicinal alcohol rinsings gets 47g ciprofloxacin HCl wet finished product.Smoke 33g ciprofloxacin HCl finished product (0.0855mol), molar yield is 80.3%.
Embodiment 4
(1) piperazine that contracts
30g cyclopropyl carboxylic acid (0.1065mol), 50g piperazine (0.5805mol), 150ml 1-Methyl-2-Pyrrolidone are dropped in the clean there-necked flask of 250ml.Stir heat temperature raising to 90～110 ℃, the about 5h of timing insulation.The monitoring of sampling liquid phase, carboxylic acid remained being controlled at below 1.5%.Insulation reaction finishes, and is cooled to 15 ± 2 ℃.Cooling is finished, and leaves standstill 3 hours, and suction filtration with 30ml * 3 medicinal alcohol rinsings, gets the wet crude product of 55～60g.
(2) salify
Above-mentioned thick wet product are dropped in the 250ml there-necked flask, add 150g water, stirring is warming up to 85 ℃, and dripping hydrochloric acid is molten substantially clear to system, adds the 1.0g gac, stirred 60 minutes, decolouring is finished, filtered while hot to the clean there-necked flask of another 250ml, acid non-soluble substance 1.0g, filter is finished, and drips refining hydrochloric acid while stirring and transfers system PH=1.0～3.5.Transfer and finish, slowly be cooled to 35 ± 2 ℃, a large amount of crystal are separated out.Suction filtration, 20ml * 2 medicinal alcohol rinsings gets 46g ciprofloxacin HCl wet finished product.Smoke 30.5g ciprofloxacin HCl finished product (0.079lmol), molar yield is 74.3%.
Embodiment 5
(1) piperazine that contracts
With 30g cyclopropyl carboxylic acid (0.1065mol), 50g piperazine (0.5805mol), 150ml 2-Pyrrolidone and diethyl carbonate mixing solutions, drop in the clean there-necked flask of 250ml.Stir heat temperature raising to 110～120 ℃, the about 10h of timing insulation.The monitoring of sampling liquid phase, carboxylic acid remained being controlled at below 1.5%.Insulation reaction finishes, and is cooled to 15 ± 2 ℃.Cooling is finished, and leaves standstill 3 hours, and suction filtration with 30ml * 3 medicinal alcohol rinsings, gets the wet crude product of 55～60g.
(2) salify
Above-mentioned thick wet product are dropped in the 250ml there-necked flask, add 150g water, stirring is warming up to 85 ℃, and dripping hydrochloric acid is molten substantially clear to system, adds the 1.0g gac, stirred 30 minutes, decolouring is finished, filtered while hot to the clean there-necked flask of another 250ml, acid non-soluble substance 0.8g, filter is finished, and dripping hydrochloric acid is transferred system pH=1.0～3.5 while stirring.Transfer and finish, slowly be cooled to 30 ± 2 ℃, a large amount of crystal are separated out.Suction filtration, 20ml * 2 medicinal alcohol rinsings gets 44g ciprofloxacin HCl wet finished product.Smoke 33.8g ciprofloxacin HCl finished product (0.0876mol), molar yield is 82.3%.
Embodiment 6
(1) piperazine that contracts
With 30g cyclopropyl carboxylic acid (0.1065mol), 50g piperazine (0.5805mol), 150ml 2-Pyrrolidone and propylene carbonate mixing solutions, drop in the clean there-necked flask of 250ml.Stir heat temperature raising to 115～120 ℃, the about 8h of timing insulation.The monitoring of sampling liquid phase, carboxylic acid remained being controlled at below 1.5%.Insulation reaction finishes, and is cooled to 10 ± 2 ℃.Cooling is finished, and leaves standstill 3 hours, and suction filtration with 30ml * 3 medicinal alcohol rinsings, gets the wet crude product of 55～60g.
(2) salify
Above-mentioned thick wet product are dropped in the 250ml there-necked flask, add 150g water, stirring is warming up to 85 ℃, and dripping hydrochloric acid is molten substantially clear to system, adds the 1.0g gac, stirred 30 minutes, decolouring is finished, filtered while hot to the clean there-necked flask of another 250ml, acid non-soluble substance 1.5g, filter is finished, and dripping hydrochloric acid is transferred system pH=1.0～3.5 while stirring.Transfer and finish, slowly be cooled to 20 ± 2 ℃, a large amount of crystal are separated out.Suction filtration, 20ml * 2 medicinal alcohol rinsings gets 43g ciprofloxacin HCl wet finished product.Smoke 31.3g ciprofloxacin HCl finished product (0.0811mol), molar yield is 76.2%.
Embodiment 7
(1) piperazine that contracts
With 30g cyclopropyl carboxylic acid (0.1065mol), 50g piperazine (0.5805mol), 150ml diethyl carbonate and N-N-methyl-2-2-pyrrolidone N-mixing solutions, drop in the clean there-necked flask of 250ml.Stir heat temperature raising to 105～110 ℃, the about 10h of timing insulation.The monitoring of sampling liquid phase, carboxylic acid remained being controlled at below 1.5%.Insulation reaction finishes, and is cooled to 15 ± 2 ℃.Cooling is finished, and leaves standstill 3 hours, and suction filtration with 30ml * 3 medicinal alcohol rinsings, gets the wet crude product of 55～60g.
(2) salify
Above-mentioned thick wet product are dropped in the 250ml there-necked flask, add 150g water, stirring is warming up to 85 ℃, and dripping hydrochloric acid is molten substantially clear to system, adds the 1.0g gac, stirred 30 minutes, decolouring is finished, filtered while hot to the clean there-necked flask of another 250ml, acid non-soluble substance 1.3g, filter is finished, and dripping hydrochloric acid is transferred system pH=1.0～3.5 while stirring.Transfer and finish, slowly be cooled to 20 ± 2 ℃, a large amount of crystal are separated out.Suction filtration, 20ml * 2 medicinal alcohol rinsings gets 42g ciprofloxacin HCl wet finished product.Smoke 31.0g ciprofloxacin HCl finished product (0.0804mol), molar yield is 75.2%.
Embodiment 8
(1) piperazine that contracts
With 30g cyclopropyl carboxylic acid (0.1065mol), 50g piperazine (0.5805mol), 150ml2-pyrrolidone and ethylene carbonate mixing solutions, drop in the clean there-necked flask of 250ml.Stir heat temperature raising to 115～120 ℃, the about 8h of timing insulation.The monitoring of sampling liquid phase, carboxylic acid remained being controlled at below 1.5%.Insulation reaction finishes, and is cooled to 20 ± 2 ℃.Cooling is finished, and leaves standstill 3 hours, and suction filtration with 30ml * 3 medicinal alcohol rinsings, gets the wet crude product of 55～60g.
(2) salify
Above-mentioned thick wet product are dropped in the 250ml there-necked flask, add 150g water, stirring is warming up to 85 ℃, and dripping hydrochloric acid is molten substantially clear to system, adds the 1.0g gac, stirred 30 minutes, decolouring is finished, filtered while hot to the clean there-necked flask of another 250ml, acid non-soluble substance 1.0g, filter is finished, and dripping hydrochloric acid is transferred system pH=1.0～3.5 while stirring.Transfer and finish, slowly be cooled to 20 ± 2 ℃, a large amount of crystal are separated out.Suction filtration, 20ml * 2 medicinal alcohol rinsings gets 44g ciprofloxacin HCl wet finished product.Smoke 31.8g ciprofloxacin HCl finished product (0.0825mol), molar yield is 77.1%.
Embodiment 9
(1) piperazine that contracts
With 30g cyclopropyl carboxylic acid (0.1065mol), 50g piperazine (0.5805mol), 150ml propyl carbinol and DMAc mixing solutions (volume ratio 9: 1), drop in the clean there-necked flask of 250ml.Stir heat temperature raising to 95～120 ℃, the about 16h of timing insulation.The monitoring of sampling liquid phase, carboxylic acid remained being controlled at below 1.5%.Insulation reaction finishes, and is cooled to 20 ± 2 ℃.Cooling is finished, and leaves standstill 3 hours, and suction filtration with 30ml * 3 medicinal alcohol rinsings, gets the wet crude product of 55～60g.
(2) salify
Above-mentioned thick wet product are dropped in the 250ml there-necked flask, add 150g water, stirring is warming up to 85 ℃, and dripping hydrochloric acid is molten substantially clear to system, adds the 1.0g gac, stirred 30 minutes, decolouring is finished, filtered while hot to the clean there-necked flask of another 250ml, acid non-soluble substance 0.5g, filter is finished, and dripping hydrochloric acid is transferred system pH=1.0～3.5 while stirring.Transfer and finish, slowly be cooled to 20 ± 2 ℃, a large amount of crystal are separated out.Suction filtration, 20ml * 2 medicinal alcohol rinsings gets 44g ciprofloxacin HCl wet finished product.Smoke 32.1g ciprofloxacin HCl finished product (0.0833mol), molar yield is 77.8%.
Embodiment 10
(1) piperazine that contracts
With 30g cyclopropyl carboxylic acid (0.1065mol), 50g piperazine (0.5805mol), 150ml propyl carbinol and DMAc mixing solutions (volume ratio 5: 5), drop in the clean there-necked flask of 250ml.Stir heat temperature raising to 95～120 ℃, the about 8h of timing insulation.The monitoring of sampling liquid phase, carboxylic acid remained being controlled at below 1.5%.Insulation reaction finishes, and is cooled to 20 ± 2 ℃.Cooling is finished, and leaves standstill 3 hours, and suction filtration with 30ml * 3 medicinal alcohol rinsings, gets the wet crude product of 55～60g.
(2) salify
Above-mentioned thick wet product are dropped in the 250ml there-necked flask, add 150g water, stirring is warming up to 85 ℃, and dripping hydrochloric acid is molten substantially clear to system, adds the 1.0g gac, stirred 30 minutes, decolouring is finished, filtered while hot to the clean there-necked flask of another 250ml, acid non-soluble substance 0.3g, filter is finished, and dripping hydrochloric acid is transferred system pH=1.0～3.5 while stirring.Transfer and finish, slowly be cooled to 20 ± 2 ℃, a large amount of crystal are separated out.Suction filtration, 20ml * 2 medicinal alcohol rinsings gets 44g ciprofloxacin HCl wet finished product.Smoke 33.0g ciprofloxacin HCl finished product (0.0856mol), molar yield is 79.9%.
The above only is the representative embodiment of the present invention, is not that the present invention is done any pro forma restriction.Every foundation technical spirit of the present invention all falls within the scope of protection of the present invention any simple modification, equivalent variations and modification that above embodiment did.
Claims (4)
1. the preparation method of ciprofloxacin HCl, its step is as follows: a) cyclopropyl carboxylic acid is added in the organic solvent, and add piperazine,, reacted 3～8 hours down at 60～120 ℃ as acid binding agent with alkali, the monitoring cyclopropyl carboxylic acid is residual less than 2% o'clock termination reaction, stirring is cooled to 0～30 ℃, leaves standstill suction filtration; B) add water and hydrochloric acid in the products therefrom toward a) step, under agitation be warming up to molten clearly, add activated carbon decolorizing, filtered while hot, and transfer filtrate pH to 2～4 with hydrochloric acid, and the cooling crystallization filters, rinsing, and drying makes ciprofloxacin HCl;
Above-mentioned a) the organic solvent described in the step is 2-Pyrrolidone, N, N-N,N-DIMETHYLACETAMIDE, N, a kind of and mixed solvent more than two kinds in dinethylformamide, propylene carbonate, diethyl carbonate, 1-Methyl-2-Pyrrolidone, N-ethyl pyrrolidone, ethylene carbonate, propyl carbinol, the n-hexyl alcohol.
2. ciprofloxacin HCl preparation method according to claim 1 is characterized in that described organic solvent is the mixed solvent of N,N-dimethylacetamide and propyl carbinol.
3. ciprofloxacin HCl preparation method according to claim 2, the volume ratio that it is characterized in that N,N-dimethylacetamide and propyl carbinol is 1: 9-5: 5.
4. ciprofloxacin HCl preparation method according to claim 1 is characterized in that a) alkali described in the step is salt of wormwood, yellow soda ash, saleratus, sodium bicarbonate, triethylamine, Tetramethyl Ethylene Diamine or pyridine.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102643250A (en) * | 2012-04-11 | 2012-08-22 | 浙江新华制药有限公司 | Recovery method of piperazine in condensation mother liquor for preparing ciprofloxacin |
| WO2012127505A2 (en) * | 2011-03-21 | 2012-09-27 | Davuluri Ramamohan Rao | Improved process for the preparation of ciprofloxacin and its acid addition salts |
| CN103420938A (en) * | 2012-05-25 | 2013-12-04 | 浙江京新药业股份有限公司 | Method for recovering piperazine after piperazine condensation reaction in quinolone medicine preparation |
| CN109232528A (en) * | 2018-09-11 | 2019-01-18 | 河南精康制药有限公司 | A kind of high efficiente callback of Sparfloxacin condensed mother liquor utilizes method |
-
2009
- 2009-07-02 CN CN200910158876A patent/CN101851198A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012127505A2 (en) * | 2011-03-21 | 2012-09-27 | Davuluri Ramamohan Rao | Improved process for the preparation of ciprofloxacin and its acid addition salts |
| WO2012127505A3 (en) * | 2011-03-21 | 2012-10-18 | Davuluri Ramamohan Rao | Improved process for the preparation of ciprofloxacin and its acid addition salts |
| CN102643250A (en) * | 2012-04-11 | 2012-08-22 | 浙江新华制药有限公司 | Recovery method of piperazine in condensation mother liquor for preparing ciprofloxacin |
| CN103420938A (en) * | 2012-05-25 | 2013-12-04 | 浙江京新药业股份有限公司 | Method for recovering piperazine after piperazine condensation reaction in quinolone medicine preparation |
| CN109232528A (en) * | 2018-09-11 | 2019-01-18 | 河南精康制药有限公司 | A kind of high efficiente callback of Sparfloxacin condensed mother liquor utilizes method |
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Open date: 20101006 |